Several substituted 2-(2-pyridylmethyl) sulfinyl-1H-benzimidazoles are known gastric proton pump inhibitors. These benzimidazole derivatives include omeprazole, lansoprazole, pantoprazole, and rabeprazole.
Lansoprazole is a reversible proton (acid) pump inhibitor. Lansoprazole per se is protected by U.S. Pat. No. 4,628,098 assigned to Takeda Chemical Industries, Ltd. Lansoprazole is known chemically as (2-[[[3-methyl-4-(2,2,2-trifluoro-ethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole) and has the following chemical formula A:
wherein R1 is methyl, R2 is trifluoro-ethoxy, and R3 is hydrogen and R4 is hydrogen. Other benzimidazole derivatives (e.g., omeprazole and pantoprazole) share lansoprazole's ability in inhibiting gastric acid secretion and they are commonly known as anti-ulcer agents.
The preparation of lansoprazole by conventional methods is always accompanied by the formation of small quantities of the corresponding sulfone derivative as an impurity. For example, U.S. Pat. No. 6,180,652 (“the '652 patent”) describes the presence of sulfone derivative. Formation of sulfone derivative brings about the drawback of low yield of the desired sulfoxide. The '652 patent describes a method that permits separation of lansoprazole from its sulfone derivative and discloses an acetone complex of the lansoprazole salt.
U.S. Pat. No. 6,002,011 (“the '011 patent”) discloses that lansoprazole and other 2-(2-pyridylmethyl) sulfinyl-benzimidazole derivatives tend to lose stability and decompose when contaminated with traces of residual solvent, particularly in their crystal structure. According to the '011 patent, the residual solvent must be reduced to a minimum and it discloses a water reslurry method which provides a ‘solvent-free’ lansoprazole said to be more stable. Specifically, it limits the lansoprazole content to no more than 500 ppm water and 200 ppm C1-6 alcohol.
The '011 patent also states that when an ethanol:water system is used to crystallize lansoprazole, it often contains solvent in excess of tolerable limits (i.e., more than 500 ppm water and more than 200 ppm alcohol) which causes the lansoprazole to be unstable. Efforts to eliminate this excessive solvent by intensive drying further destabilize the lansoprazole. As such, this prepared lansoprazole still contains intolerable levels of solvent and is unsuitable to be a pharmaceutical composition.
Reducing water and ethanol to levels below the reported tolerable limits (i.e., more than 500 ppm water and more than 200 ppm alcohol) is both time-consuming and costly.
In “Stabilization of a New Antiulcer Drug (Lansoprazole) in Solid Dosage Forms,” by Tabata et al., Drug Development and Industrial Pharmacy, 18(13) 1437-47 (1992) (the ‘Tabata article’), the mechanism of stabilization of lansoprazole in enteric granules is discussed. The Tabata article discloses that lansoprazole is unstable under conditions of high temperature and also high humidity, with a decrease in the amount of lansoprazole and discoloration of the material being noted on storage under such conditions. The variation in assay and color of solid lansoprazole over time on storage at various temperatures and humidities is presented in Table 2, at page 1439. The table shows that after 4 months at 40° C. and 75% room humidity lansoprazole turns pale brown, and even in the absence of humidity under the same conditions, lansoprazole turns pale yellowish brown. The Tabata article explains the unusually high instability of lansoprazole under even weak acidic conditions as being due to proton attack on the sulfoxide group. Lansoprazole seems to be especially sensitive to such attack compared to the other members of the 2-(2-pyridylmethyl) sulfinyl-benzimidazole family of drugs.
Lansoprazole is a relatively unstable compound, especially in acidic conditions, but also under strongly basic conditions. The Tabata article further discloses that degradation of lansoprazole is minimized under weakly basic conditions, and concludes that the degradation of lansoprazole in dosage forms is minimized by it being formulated to also contain stabilizing compounds suitable to produce such a weakly basic pH. The Tabata article, however, does not address the use of lansoprazole as an active pharmaceutical ingredient. As such, lansoprazole must be stored and transported, often for long time periods.
There is a continuing need to obtain a stable 2-(2-pyridylmethyl) sulfinyl-1H-benzimidazole (e.g., lansoprazole) that is free of contaminants (e.g., sulfone and sulfide derivatives) and a long-felt need for a pharmaceutical composition containing such a stable lansoprazole. In other words, the need exists for a stable form of lansoprazole, which does not suffer degradation and/or discoloration even if stored or transported under non-optimum conditions. The present invention provides such a stable lansoprazole compound and a method for its production.